Alkaloid Composition for E-Cigarette

ABSTRACT

An alkaloid composition for an e-cigarette contains a solvent and at least about 25 wt. % anatabine based on the total alkaloid weight of the composition. The alkaloid composition may be contained in a refilling cartridge for an e-cigarette, or in a container as part of a kit for refilling an e-cigarette. The alkaloid compositions disclosed herein feature a balanced form of alkaloids to provide an attractive alternative to smoking tobacco, in which nicotine makes up about 90 wt. % of the total alkaloid content. The alkaloid compositions are characterized by a significant quantity of anatabine, which has lower toxicity than other alkaloids such as nicotine. The alkaloid compositions enable individuals to experience the pleasure-enhancing attributes of conventional cigarette smoking, while avoiding exposure to combusted materials and other potentially hazardous components present in tobacco.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 13/493,132, filedJun. 11, 2012, which claims benefit under 35 U.S.C. § 119(e) to U.S.Application No. 61/500,237, filed Jun. 23, 2011, the disclosure of eachof which is hereby incorporated by reference in its entirety.

BACKGROUND

Combustion of organic materials such as tobacco is known to produce tarand other potentially harmful materials. Electronic cigarettes (or“e-cigarettes”) have been developed as an alternative to traditionalcigarettes as a means for volatizing active components, such asnicotine, for inhalation without combustion, while at the same timeproviding the user with an oral experience similar to that oftraditional cigarette smoking. U.S. Pat. No. 7,832,410 B2 to Hondescribes an e-cigarette having a liquid supply bottle in communicationwith an atomizer for volatizing a nicotine-containing solution. U.S.Pat. No. 7,726,320 B2 to Robinson et al. discloses a smoking articlehaving an electrically powered aerosol-generating device which heatstobacco contained within the device to generate an aerosol which isdescribed as being similar to tobacco smoke.

Current e-cigarettes generally use a liquid containing nicotine, a toxicand addictive substance, as the sole active component. It also has beenproposed to use so-called whole tobacco alkaloid e-liquid, containingnicotine in proportions similar to those existing in tobacco (e.g., ≥90wt. % of alkaloid content). The art has recognized a need fornon-nicotine or reduced-nicotine alternatives to tobacco and tobaccoreplacement products. See D. K. Hatsukami et al., “Nicotine reductionrevisited: science and future directions,” Tobacco Control 19: e1-e10(2010). It would be especially desirable to develop non-nicotine orreduced-nicotine alternatives that more effectively achieve thepleasure-enhancing attributes of traditional cigarette smoking, which inturn may assist smokers in quitting traditional cigarette smoking.

SUMMARY

Embodiments of the present invention are directed to e-cigarettes,alkaloid compositions for e-cigarettes, and refilling cartridges fore-cigarettes containing certain alkaloid compositions. In one aspect, arefilling cartridge for an e-cigarette contains a liquid alkaloidcomposition comprising a solvent and at least about 25 wt. % anatabinebased on the total alkaloid weight of the composition.

In another aspect, a kit for refilling an e-cigarette comprises (i) aliquid alkaloid composition comprising a solvent and at least about 25wt. % anatabine based on the total alkaloid weight of the composition,and (ii) instructions for filling the liquid alkaloid composition into aliquid receptacle of an e-cigarette.

In another aspect, a method of refilling an e-cigarette includes thesteps of (i) providing a liquid alkaloid composition comprising asolvent and at least about 25 wt. % anatabine based on the totalalkaloid weight of the composition, and (ii) filling the liquid alkaloidcomposition into a liquid receptacle of an e-cigarette.

In yet another aspect, an e-cigarette comprises a cartridge containing aliquid alkaloid composition comprising a solvent and at least about 25wt. % anatabine based on the total alkaloid weight of the composition.The e-cigarette may be of a single-use or disposable type, or may berefillable with liquid alkaloid compositions to facilitate reuse.

Other aspects relate to non-tobacco products that contain an alkaloidcomposition comprising about 25 wt. % to about 95 wt. % anatabine, andabout 5 wt. % to about 75 wt. % of a second alkaloid, based on the totalalkaloid weight of the composition. The second alkaloid may be nicotine,nornicotine, anabasine, or a combination of two or more of them. Thenon-tobacco product may be in the form of a solid bit of compressedpowder, chewing gum, gelcap, capsule, pill, lozenge, or the like.

The alkaloid compositions disclosed herein feature different ranges ofalkaloids to provide an attractive alternative to smoking conventionale-cigarettes, in which nicotine makes up about 90 to 100 wt. % of thetotal alkaloid content. The disclosed alkaloid compositions arecharacterized by a significant quantity of anatabine, which has lowertoxicity and risk of abuse as compared to other alkaloids such asnicotine. The alkaloid compositions enable individuals to experience thepleasure-enhancing attributes of conventional cigarette smoking, whileavoiding exposure to combusted materials and other potentially hazardouscomponents present in tobacco. As a result, individuals may be morelikely to quit conventional cigarette smoking.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present invention and certainadvantages thereof may be acquired by referring to the followingdetailed description in consideration with the accompanying drawings, inwhich:

FIG. 1 is a schematic illustration of one example of an e-cigaretteconfiguration.

DETAILED DESCRIPTION

Tobacco is among the most chemically complex substances known, withtobacco and tobacco smoke containing more than 8,000 compounds. Inaddition to nicotine, tobacco contains the minor alkaloids nornicotine,anabasine, and anatabine. While nicotine is regarded as the principaladdictive component in tobacco, a variety of other factors also arebelieved to contribute to tobacco addiction. For example, tobacco smokehas been reported to have a monoamine oxidase (MAO) inhibitory effect.MAO is an enzyme involved in the breakdown of dopamine, apleasure-enhancing neurotransmitter. See J. S. Fowler et al.,“Inhibition of Monoamine Oxidase B in the Brain of Smokers,” Nature(Lond), 379(6567):733 736 (1996); J. Stephenson, “Clues Found to TobaccoAddiction,” Journal of the American Medical Association, 275(16):1217-1218 (1996). See also Williams et al. U.S. Pat. No. 6,350,479.

Aspects of the present invention are directed to alkaloid compositionsfor e-cigarettes which are designed to provide different ranges ofalkaloids to more effectively achieve the pleasure-enhancing effectsthat smokers obtain through smoking traditional cigarettes, whileavoiding or reducing exposure to nicotine. In one embodiment, thealkaloid composition comprises at least about 25 wt. % anatabine basedon the total alkaloid weight. In some examples, anatabine is the solealkaloid present in the composition, e.g., anatabine comprises 100 wt. %of the total alkaloid weight. In other examples, up to about 75 wt. % ofone or more other alkaloids, such as nicotine, nornicotine, and/oranabasine, may be present in addition to anatabine. For example,anatabine and nicotine may be combined in a weight ratio(anatabine-to-nicotine) of about 50:1 to about 1:3, or from about 25:1to about 1:2, from about 10:1 to about 3:2, or from about 5:1 to about1:1.

Unless otherwise clear from context, all percentages referred to hereinare expressed as percent by weight based on the total weight of thecomposition.

Anatabine may be prepared synthetically, such as via a benzophenoneiminepathway as described in Puthiaparampil et al. U.S. Pat. No. 8,207,346,the disclosure of which is incorporated herein by reference in itsentirety. Anatabine may be present in the form of a racemic mixture oras isolated enantiomer, e.g., R-(+)-anatabine or S-(−)-anatabine, and/oras one or more pharmaceutically acceptable (or food grade) salts ofanatabine. Unless otherwise clear from context, “anatabine” as usedherein refers to racemic mixtures of anatabine, enantiomers ofanatabine, salt and non-salt forms of anatabine, as well as salt andnon-salt forms of anatabine enantiomers. Non-limiting examples ofpossible salts are described in P. H. Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection and Use,Weinheim/Zürich:Wiley-VCH/VHCA, 2002, including salts of1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid(L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoricacid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid),caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconicacid (D), glucuronic acid (D), glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid,lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid(DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid,oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionicacid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearicacid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid,toluenesulfonic acid (p), and undecylenic acid.

As an alternative to synthetic preparation, anatabine may be obtained byextraction from tobacco or other plants, such as members of theSolanaceae family, such as datura, mandrake, belladonna, capsicum,potato, tomato, nicotiana, eggplant, and petunia. A tobacco extract maybe prepared from cured tobacco stems, lamina, or both. Flue (bright)varieties of tobacco are often used, i.e., Virginia flue. Other tobaccovarieties may be used, such as Burley, dark-fired, and/or othercommercial tobacco varieties. Two or more tobacco varieties may becombined to form a blend. In the extraction process, cured tobaccomaterial is extracted with a solvent, typically water, ethanol, steam,or carbon dioxide. The resulting solution contains the solublecomponents of the tobacco, including alkaloids such as anatabine.Anatabine may be purified using known techniques such as liquidchromatography.

The amount of anatabine present in the composition may vary depending onfactors such as the type of e-cigarette and whether other activecomponents, such as nicotine and/or other alkaloids, are present. By wayof example, the amount of anatabine may range from about 0.1 to about 25mg, from about 0.5 to about 20 mg, or from about 1 to about 10 mg, pertotal gram of composition.

As described in U.S. Pat. No. 8,241,680 to Williams et al., compositionscontaining anatabine were found to be efficacious for the temporaryreduction of tobacco cravings, even without the presence of nicotine.Anatabine and other minor alkaloids also have been reported to bind tonicotinic receptors. See “Receptors for Nicotine in the Central NervousSystem: 1 Radioligand Binding Studies,” Group Research & DevelopmentCentre, British-American Tobacco Co. Ltd. (1984).

In addition to anatabine, the composition may contain up to about 75 wt.% of one or more other alkaloids, such as nicotine, nornicotine, and/oranabasine, based on the total alkaloid weight. Such alkaloids may beextracted from tobacco or other plant materials and purified using knowntechniques, and/or prepared synthetically using known synthesis methods.Anatabine and additional alkaloid(s), such as nicotine, may be combinedin a weight ratio (anatabine-to-total other alkaloids) of about 50:1 toabout 1:3, or from about 25:1 to about 1:2, from about 10:1 to about3:2, or from about 5:1 to about 1:1.

The composition typically contains other components such as water,organic solvents, sweetening and/or flavoring agents, and the like.Examples of solvents that are commonly used in liquid compositions fore-cigarettes include polyhydric alcohols such as 1,2-propylene glycol(PG or MPG); monohydric alcohols such as ethanol; ethyl acetate; and thelike. The amount of water present typically ranges from about 0.1 toabout 10 wt. %, usually from about 0.5 to about 5 wt. %. The amount oforganic solvent present typically ranges from about 50 to about 99 wt.%, often from about 75 to about 95 wt. %.

If desired, one or more flavorants may be added to the composition,non-limiting examples of which include peppermint, menthol, wintergreen,spearmint, propolis, eucalyptus, cinnamon, or the like. The total amountof flavorants typically ranges from about 0.5 to about 15 wt. %, oftenfrom about 1 to about 10 wt. %, based on the total weight of thecomposition.

The e-cigarette may be of various types of configurations, the detailsof which form no part of the present invention. In general, e-cigarettesmay be of a single-use or disposable type, or may be refillable withliquid alkaloid compositions and/or cartridges containing liquidcompositions to facilitate reuse. One example of an e-cigarette is shownin FIG. 1. An air inlet 4 is provided on the external wall of a shell 14which houses LED 1, cell 2, electronic circuit board 3, normal pressurecavity 5, sensor 6, vapor-liquid separator 7, atomizer 9,liquid-supplying bottle 11, mouthpiece 15, microswitch 16, gas vent 17,and air passage 18. The electronic circuit board 3 has an electronicswitching circuit and a high frequency generator. A negative pressurecavity 8 is provided in the sensor 6 and is separated from the sensor 6by a ripple film. An atomization cavity 10 is provided in the atomizer9. A retaining ring 13 is provided for locking the liquid-supplyingbottle 11 between one side of the liquid-supplying bottle 11 and theshell 14; and an aerosol passage 12 is provided on the other side of theliquid-supplying bottle. Other details are described in U.S. Pat. No.7,832,410 B2 to Hon, the disclosure of which is hereby incorporated byreference in its entirety.

By providing a balanced alkaloid composition containing anatabine as asignificant alkaloid component, it is possible to prepare e-cigarettesthat reduce cravings for traditional tobacco smoking, while minimizingtoxicity and other undesirable side effects associated with nicotine andother tobacco components. The e-cigarette may be used as needed tosatisfy cravings, or at intervals such as once daily, twice daily, orthree or more times daily, depending on such factors as theconcentration of active components and the subject's physiologicalconditions.

In an alternative embodiment, a non-tobacco formulation contains analkaloid composition comprising about 25 wt. % to about 95 wt. %anatabine, and about 5 wt. % to about 75 wt. % of a second alkaloid,based on the total alkaloid weight of the composition. The secondalkaloid may be nicotine, nornicotine, anabasine, or a combination oftwo or more of them. The non-tobacco product may be in the form of asolid bit of compressed powder, chewing gum, capsule, pill, lozenge, orthe like. The term “non-tobacco” means that the product is essentiallyfree of tobacco leaf or tobacco extract, except however that some or allof the alkaloids present in the non-tobacco product may be extractedfrom tobacco and purified using conventional techniques such as liquidchromatography.

Additional components ingredients may be added to the non-tobaccoproducts to improve taste or stability. Such additional componentsinclude, but are not limited to, sweeteners, natural flavorants,artificial flavorants, colorants, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, odorants, opacifiers, suspendingagents, binders, thickeners, and mixtures thereof, including, but notlimited to, xanthum gum, carboxymethylcellulose, carboxyethylcellulose,hydroxypropylcellulose, methylcellulose, microcrystalline cellulose,starches, dextrins, fermented whey, tofu, maltodextrins, polyols(including sugar alcohols, such as sorbitol or mannitol), carbohydrates(e.g., lactose), propylene hlycol alginate, gellan gum, guar, pectin,tragacanth gum, gum acacia, locust bean gum, gum arabic, gelatin,mannitol, natural and/or artificial mint flavors, sucralose, silicondioxide, stearic acid, hydroxypropyl methylcellulose, magnesiumstearate, titanium dioxide, natural glaze, methylparaben,propylparabens, triethyl citrate, citric acid, butylated hydroxytoluene(BHT), mono and diglycerides, polysorbate 80, and the like.

The non-tobacco products may be in a variety of forms, e.g., to be takenorally, such as pills, tablets, capsules, soft gels, gelcaps, liquids,syrups, suspensions, powders, chews, lozenges, gum, bars, etc., or to beadministered by other routes, such as parenterally, by inhalation spray,topically, via an implanted reservoir, etc. The alkaloid compositionsalso can be prepared to be administered in foods or beverages. Forexample, they can be supplied as a dried or powdered product forreconstitution with water or other suitable vehicle before use (e.g.,milk, fruit juice, and the like).

Examples 1-8

Alkaloid compositions for e-cigarettes may be prepared by combining thecomponents listed in Table 1 below and mixing to form a solution.Anatabine may be prepared synthetically as described in Examples 1-3 ofU.S. Pat. No. 8,207,346. Nicotine, anabasine, and nornicotine may beextracted from tobacco materials and purified using known techniques.

TABLE 1 Example 1 2 3 4 5 6 7 8 Anatabine 10 8 4 6 7 12 8 6 (mg)Nicotine — 4 8 4 5 6 — 4 (mg) Nornicotine — — — — — — 4 2 (mg) Anabasine— — — 3 1 1 — 2 (mg) Polyethylene 91 90 92 93 92 94 91  90 Glycol (g)Ethyl acetate 0.5 0.5 — 0.5 0.4 0.5 — 0.4 (g) Water (g) 4 4.5 3.5 4 2.53.5 5 4.5 Flavors (g) 1 1.25 1.5 1 1 1.5   0.75 1.25

The compositions described in Examples 1-8 may be filled into refillingcartridges for e-cigarettes, or filled into a liquid container that isused as part of a kit for refilling liquid receptacles in e-cigarettes.The compositions alternatively may be filled into a single-use ordisposable type of e-cigarette.

While the invention has been described with respect to specificexamples, those skilled in the art will appreciate that there arenumerous variations and permutations of the above described systems andtechniques that fall within the spirit and scope of the invention as setforth in the appended claims.

What is claimed is:
 1. An e-cigarette refilling cartridge containing aliquid alkaloid composition comprising a solvent and an active componentcomprising at least about 95 wt. % anatabine based on the total weightof the active component.
 2. The e-cigarette refilling cartridge of claim1, wherein the anatabine is synthetic anatabine.
 3. The e-cigaretterefilling cartridge of claim 1 wherein anatabine is provided in the formof an extract of a plant selected from the group consisting of tobacco,datura, mandrake, belladonna, capsicum, potato, tomato, nicotiana,eggplant, and petunia.
 4. The e-cigarette refilling cartridge of claim1, wherein the solvent is 1,2-polyethylene glycol.
 5. The e-cigaretterefilling cartridge of claim 1, wherein the solvent further comprisesethyl acetate.
 6. The e-cigarette refilling cartridge of claim 1,wherein the liquid alkaloid composition further comprises an alkaloidselected from the group consisting of nicotine, nornicotine, anabasine,and combinations thereof.
 7. The e-cigarette refilling cartridge claim1, wherein anatabine comprises 100 wt. % of the active component.
 8. Thee-cigarette refilling cartridge of claim 1, wherein the liquid alkaloidcomposition further comprises 0.5 to about 15 wt. % of one or moreflavorants based on the total weight of the composition.
 9. Thee-cigarette refilling cartridge of claim 8, wherein the one or moreflavorants are selected from the group consisting of peppermint,menthol, wintergreen, spearmint, propolis, eucalyptus, and cinnamon. 10.An e-cigarette comprising a reservoir containing a liquid alkaloidcomposition comprising a solvent and an active component comprising atleast about 95 wt. % anatabine based on the total weight of the activecomponent.
 11. The e-cigarette of claim 10, wherein the anatabine issynthetic anatabine.
 12. The e-cigarette of claim 10 wherein anatabineis provided in the form of an extract of a plant selected from the groupconsisting of tobacco, datura, mandrake, belladonna, capsicum, potato,tomato, nicotiana, eggplant, and petunia.
 13. The e-cigarette of claim10, wherein the solvent is 1,2-polyethylene glycol.
 14. The e-cigaretteof claim 10, wherein the solvent further comprises ethyl acetate. 15.The e-cigarette of claim 10, wherein the liquid alkaloid compositionfurther comprises an alkaloid selected from the group consisting ofnicotine, nornicotine, anabasine, and combinations thereof.
 16. Thee-cigarette of claim 10, wherein anatabine comprises 100 wt. % of theactive component.
 17. The e-cigarette of claim 10, wherein the liquidalkaloid composition further comprises 0.5 to about 15 wt. % of one ormore flavorants based on the total weight of the composition.
 18. Thee-cigarette of claim 17, wherein the one or more flavorants are selectedfrom the group consisting of peppermint, menthol, wintergreen,spearmint, propolis, eucalyptus, and cinnamon.